Parathyroid hormone (PTH) dramatically increases bone formation but also increases bone resorption and causes hypercalcemia. PTH's anabolic actions may make this hormone an attractive part of strategies designed to restore the lost bone of osteoporotics. Incomplete understanding of the mechanisms of PTH action limit its effective use however. This SCOR proposes to define better the actions of parathyroid hormone (PTH) in humans and to use genetically manipulated animals to learn how PTH functions in living bone, in order to exploit fully the therapeutic potential of PTH. Project I: Bone formation-resorption coupling and osteoporosis (Robert Neer, PI) will address the relationship between PTH's anabolic and catabolic actions in osteoporotic women to explore basic mechanisms and to improve current therapies. Project II: Anabolic actions of PTH in early post-menopausal women (Joel Finkelstein, PI will define the actions of PTH on the normal bone of women who have recently become estrogen deficient. This work will provide insight into PTH action and how age and bone loss affect the response to PTH. Project Ill PTH action and skeletal collagen degradation (Stephen Krane, PI) will use mice resistant to collagenase to define the role of matrix resorption in the anabolic actions of PTH and of interstitial collagenase in normal bone physiology. Project IV: Osteoblast-specific ablation of the PTH/PTHrP receptor (Henry Kronenberg, PI) will use the cre-lox system to ablate the PTH/PTHrP receptor gene from populations of cells in the osteoblast lineage in living mice to define the cell-cell cooperation needed for responses to PTH and PTHrP. Project V: Constitutively active PTH/PTHrP receptors in osteoblasts (Ernestina Schipani, PI) will use transgenic animals expressing a constitutively active PTH/PTHrP receptor in different populations of cells of the osteoblast lineage to define how activation of this receptor in osteoblasts leads to anabolic and catabolic actions of PTH. A Bone Analysis Core Facility (Beate Lanske, PI) will provide expert and efficient histologic analysis of bone and performance of serological tests. These projects and associated cores should lead to more effective use of anabolic agents in the treatment of osteoporosis.